1. Field of the Invention
This invention relates to novel bicyclonucleoside analogues which are useful for synthesis of non-natural oligonucleotide analogues which exhibit excellent anti-sense or anti-gene activity and in vivo stability.
This invention relates to novel oligonucleotide analogues which have one or more of said bicyclonucleoside moieties.
Further, this invention relates to novel modified bicyclonucleoside analogues which exhibit anti-AIDS activity.
2. Background Art
Oligonucleotides having excellent anti-sense or anti-gene activities and in vivo stability have been expected to be useful medicaments.
However, it is well known that natural oligonucleotides are rapidly decomposed by various nucleases in the blood or cells.
To solve these problems, numerous non-natural oligonucleotide analogues have been synthesized, and it has been tried to develop them as medicaments. For example, oligonucleotides wherein the oxygen atom binding to the phosphorus atom of the phosphodiester linkage is substituted by a sulfur atom, a methyl group, or a boron atom, are known. Further, oligonucleotides whose sugar and/or base moieties are chemically modified are also known.
More concretely, ISIS Co. has developed a thioate oligonucleotide, ISIS2922, as a therapeutic agent for retinitis infected by human cytomegalovirus and this has been sold as “VITRAVENE” (trade name in the United States).
Any non-natural oligonucleotide analogues described above, however, have not been fully satisfactory due to their insufficient potency of anti-sense or anti-gene activity, (i.e., ability to form complementary strands with mRNA or DNA) and stability to various nucleases, and due to side effects caused by non-selective binding to various proteins in vivo. Thus it has been desired to develop non-natural oligonucleotide analogues having more potent anti-sense or anti-gene activities, in vivo stability, and fewer side effects.
Compounds having a dioxabicyclo[2,2,1]heptane moiety which is related to that of the present invention and which is shown below are described in WO98/39352. These compounds differ from the compounds of the present invention in the substituent at the 3′ position of ribose. Further, it has not been known that these compounds exhibit anti-AIDS activity.

wherein Bo indicates a pyrimidine or purine nucleic acid base or their analogues, X and Y are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group, an acyl group or a silyl group.
An objective of the present invention is to provide novel bicyclonucleoside analogues which are useful for synthesis of non-natural oligonucleotides which exhibit excellent anti-sense or anti-gene activity and in vivo stability.
An objective of the present invention is also to provide novel oligonucleotide analogues having 1 or more relevant bicyclonucleoside moieties.
Furthermore, another objective of the present invention is to provide novel bicyclonucleoside analogues having anti-AIDS activity.
The present inventors have performed painstaking research to complete these objectives, and found that novel bicyclonucleoside analogues having a 2′-O,4′-C-methylene moiety are important intermediate compounds to synthesize non-natural oligonucleotides which have excellent anti-sense or anti-gene activity, as well as in vivo stability. Further, the present inventors found that the novel oligonucleotide analogues having one or more of said bicyclonucleoside moieties exhibit excellent anti-sense or anti-gene activity as well as in vivo stability. Further, said bicyclonucleoside analogues have excellent anti-AIDS activity. Thus the present inventors have completed the present invention.